Remote sensing tonometric catheter method

ABSTRACT

The method is accomplished by introducing the catheter (20) into the organ such that the sampling chamber (40) is disposed at a portion of the wall of the organ. The sampling chamber (40) is left in position at the wall of the organ for a time sufficient to allow the fluid or gas of interest to diffuse into the sampling chamber (40). The concentration of the liquid fluid or gaseous fluid of interest is analyzed. The pH of the wall of the organ may be calculated based on the concentration of the fluid or gas property of interest.

This application is the U.S. national stage of PCT application PCT/U.S.Ser. No. 97/02953, filed Mar. 18, 1994, which application is acontinuation-in-part of U.S. patent application Ser. No. 08/035,020,filed Mar. 22, 1993, now abandoned, which was a continuation-in-part ofU.S. patent application, Ser. No. 08/014,624, filed Feb. 8, 1993, nowabandoned, which was a continuation-in-part of copending U.S. patentapplication, Ser. No. 08/719,097, filed Jun. 20, 1991, now abandoned,which was a continuation-in-part of copending U.S. patent application,Ser. No. 08/994,721, filed Dec. 22, 1992, now abandoned.

This application hereby expressly incorporates by reference, thedisclosure and drawings of the following issued U.S. patents: U.S. Pat.Nos. 4,221,567; 4,233,513; 4,273,636; 4,423,739; 4,576,590; 4,480,190;4,596,931; 4,643,192; 4,671,287 4,859,858; 4,859,859; 4,907,166;4,914,720; 5,042,522; 5,067,492; 5,095,913; 5,158,083; 5,174,290; and5,186,172.

BACKGROUND AND SUMMARY OF THE INVENTION

This invention relates to medical diagnostic equipment and methods andis particularly concerned with hollow viscus tonometry and remoteelectronic and optical sensing.

Until the advent of the tonometric method (see U.S. Pat. No. 4,643,192,issued Feb. 17, 1987) few considered any aspect of acid-base balancewhen attempting to monitor or maintain the adequacy of tissueoxygenation. Yet acid-base balance is primarily determined by thebalance between the protons released during the release of energy by ATPhydrolysis and the resynthesis of ATP by oxidative phosphorylation. Thehydrolysis of ATP generates 150,000 mmols of H+ each day in a resting 70Kg man. All, but the 1% of this fixed acid load excreted by the kidneyseach day, is presumed to be consumed in the resynthesis of ATP byoxidative phosphorylation. When the delivery of oxygen fails to satisfythe energy needs of the tissue the rate of ATP hydrolysis exceeds therate of synthesis and the pH falls as the degree of unreversed ATPhydrolysis increases.

Information for determining global tissue oxygenation has been collectedfor many years. Eoda, D., "`Gastrotonometry` an Aid to the Control ofVentilation During Artificial Respiration," The Lance: (1959). However,it is now widely accepted that global measurements of oxygen delivery,consumption and extraction do not provide reliable information about theadequacy of local or even "global" tissue oxygenation in patients. Theindirect measurement of gastric intramucosal pH (pHi) as described inU.S. Pat. Nos. 4,643,192; 5,158,083; 5,186,172 provides clinicians witha minimally invasive yet sensitive means of detecting the development ofa tissue acidosis, and hence inadequacy of tissue oxygenation, in aregion of the body that is one of the first to exhibit an inadequacy oftissue oxygenation in shock. Use of the measurement has revealed thatsome 50% to 60% of patients having major surgery and 80% of ICU patientsdevelop an intramucosal acidosis during their illness despite theconventional appearance of being adequately resuscitated.

The degree and duration of the presence of a gastric intramucosalacidosis are highly sensitive measures of the risk of developingischemic gut mucosal injury and its putative consequences, namely thetranslocation of bacteria and their toxins, cytokine release, organdysfunctions and failures, and death from the organ failures. Byproviding an index of the adequacy of tissue oxygenation in one of thefirst parts of the body to exhibit dysoxia in shock the measurement ofgastric intramucosal pH improves the opportunity to obtain advanced andaccurate warning of impending complications and to intervene in time toprevent them. More importantly timely therapeutic measures that restorethe intramucosal pH to normality and "gut-directed" therapiesincorporating measures that reverse an intramucosal acidosis areassociated with an improved outcome. "pH-directed" therapy has inaddition been shown to improve outcome in a prospective randomizedmulticenter study of medical and surgical ICU patients.

The measurements of gastric intramucosal pH have revealed deficienciesin currently accepted practices. It has, for example, become apparentthat empirical increases in global oxygen delivery may be redundant insome 40% to 50% of patients having major cardiovascular surgery who donot develop a gastric intramucosal acidosis and whose prognosis isexcellent. It is further apparent that the vogue of increasing globaloxygen delivery to supranormal levels cannot be relied upon to preventor to reverse the presence of an intramucosal acidosis. Of particularconcern is the intramucosal acidosis that may be induced by measures,notably the transfusion of red blood cells and dobutamine, that increaseglobal oxygen delivery in patients who do not have an intramucosalacidosis but whose global oxygen delivery is considered too low.

THE TONOMETRIC METHOD

The measurement of pH in the most superficial layer of the mucosa isobtained indirectly by measuring the partial pressure of carbon dioxide(pCO₂ ; PCO₂) in the lumen of the gut and the bicarbonate concentrationin arterial blood and substituting these two values in theHenderson-Hasselbalch equation or some modification thereof. See"Gastric Intramucosal pH as a Therapeutic Index of Tissue Oxygenation inCritically Ill Patients," Lancet 1992; 339; 195-99, incorporated hereinby reference. The indirect measurement of the pH of the wall of theorgan (pH indirect or intramucosal pH) may be employed because it isbelieved or assumed that the pCO₂ in the most superficial layers of themucosa is in equilibrium with that in the lumenal contents with which itis in contact. It is further based upon the assumption that thebicarbonate concentration in the tissue is the same as that beingdelivered to it in arterial blood and that the pKa, 6.1, is the same asthat in plasma.

At present, measurements of pCO₂ in the lumen of the stomach areobtained by infusing saline into the silicone balloon of agastrointestinal tonometer, allowing the PCO₂ in the saline toequilibrate with that in the lumen of the gut; recording theequilibration time; aspirating the saline; measuring the pCO₂ in thesaline with a blood gas analyzer; using a nomogram to derive thesteady-state adjusted pCO₂ from the equilibration time and the measuredpCO₂ ; and then derive the intramucosal pH from the steady-stateadjusted pCO₂ obtained and the bicarbonate concentration in asubstantially contemporaneous sample of arterial blood. Again, see U.S.Pat. Nos. 4,643,192, issued Feb. 17, 1987; 5,174,290, issued Dec. 29,1992; and 5,186,172, issued Feb. 16, 1993; as well as copending U.S.Applications, Ser. No. 719,097, filed Jun. 20, 1991; Ser. No. 994,721,filed Dec. 22, 1992 and Ser. No. 014,624, filed Feb. 8, 1993; all threeissued patents being completely and expressly incorporated herein byreference. The precision of the measurement of gastric intramucosal pHbetween healthy subjects is excellent, the gastric intramucosal pH in ahealthy subject being the same as the pH in his arterial blood.

The prior art (see U.S. Pat. No. 4,643,192) has recognized thatintestinal ischemia, and to a lesser degree, stress ulceration, are twoproblems that plague physicians involved in the management of patientsin intensive care units. Intestinal ischemia, in particular, has aninsidious onset and may not be detected until days after the intestinehas become completely and irreversibly compromised. A delay in thediagnosis of intestinal ischemia may have devastating consequences for apatient. The availability of means for early diagnosis and management ofpatients with these problems would have immediate applicability in allintensive care units, especially where the procedure can be convenientlyconducted with reasonable safety and reliability.

It has been established that a fall in the intramucosal pH may precedethe development of intestinal ischemia and stress ulceration. Asdiscussed in U.S. Pat. No. 4,643,192, which is expressly incorporatedherein by reference, entitled "Hollow Viscus Tonometry" a fall inintramucosal pH also occurs within minutes of inducing intestinalischemia in dogs. The fall in pH in intestinal mucosa, and hence thelikelihood of ischemia or stress ulceration, can be reliably calculatedfrom a PCO₂ (partial pressure of CO₂), or other indicia of pH, inlumenal fluid and the bicarbonate concentration in arterial blood. Themethod of calculating the pH in intestinal mucosal tissue, pursuant toprinciples set forth in prior related patents discussed herein, has beenvalidated by directed measurements under a variety of conditionssimulating clinical problems. A correlation coefficient on the order of0.92 to 0.95 has been obtained in each of 16 dogs. The validity of theprocedure is inherently extensible to humans, and indeed may also beuseful in assessing the vitality of other hollow organs and tissue. SeeR. G. Fiddian-Green et al. "Splanchnic Ischemia and Multiple OrganFailure".

To measure the pCO₂ in the lumen of the gut it has heretofore beennecessary to obtain and remove a sample of fluid that has been incontact with the wall of the gut for a certain time period, usually atleast half an hour. It has now been observed that it is somewhatdifficult to manually aspirate the sampling fluid or medium from atonometric catheter located in the gut or other internal focus with anyconsistency. It is much easier to obtain such samples from the stomach,but samples obtained from the stomach frequently contain foreignmaterial that can damage a gas analyzer.

As taught in prior related patents discussed herein, the desired sampleor samples can be obtained from the gut using a catheter tube (called atonometric catheter) having a walled sampling chamber on the tube withthe sampling chamber being in sample-specific communication with thehollow interior of the tube. The wall of the sampling chamber comprisesa material which is substantially impermeable to liquid yet is highlypermeable to gas. One suitable material is polydimethylsiloxaneelastomer.

In use the catheter is introduced into a patient to place the samplingchamber at a desired site within the gut (or other hollow organ). Anaspirating liquid or medium is employed to fill the interior of thesampling chamber. The sampling chamber is left in place at the desiredsampling site long enough to allow the gases present to diffuse throughthe wall of the sampling chamber into the aspirating liquid. The timeshould be long enough for the gases to equilibrate. The liquidimpermeable nature of the sample chamber wall material prevents both theaspirating liquid from leaking out of the chamber and also the intrusionof any liquids into the aspirating liquid. After the appropriate ordesired amount of placement time has elapsed the aspirating liquid isaspirated along with the gases which have diffused into it. The samplethus obtained is analyzed for gas content, in particular for pCO₂. Inthis way the pCO₂ within the lumen of the gut can be reliably measuredwith the fluid being free from lumenal debris.

In carrying out the diagnostic method taught in prior related patents,the pCO₂ measurement is utilized in conjunction with a measurement ofthe bicarbonate ion concentration (HCO₃ ⁻) in an arterial blood sampleof the patient for determining the pH of the tract wall.

Depending upon the particular condition of a given patient, the cathetermay be left in place and samples may be taken at periodic intervals sothat pH values may be periodically calculated. The procedure has a highreliability in accurately determining the adequacy of organ tissueoxygenation, and diagnosing intestinal ischemia in its incipient stages.Such determination or detection can be useful in treating the patient sothat the potentially devastating consequences resulting from less timelydetection may often be avoided.

While the sampling techniques taught in the prior related patentsdiscussed herein have provided highly accurate and reliable results, ithas now been observed that there are instances (in the care of thecritically ill in intensive care units, for example) in which remotesensing of the organ or organ-wall condition and automatic determinationor calculation of the organ or organ-wall pH would be advantageous andeasier to effectuate. This method would thus partially or totallyeliminate the need for the somewhat cumbersome manual aspiration of thesampling fluid or medium which fills the sampling chamber. There is alsoa need to extend the benefits of tonometric sampling and sensing toother internal hollow viscus organs. To this end, there is a need fornew and different tonometric devices specifically adapted to allowsensing and sampling techniques to be performed with ease in a clinicalenvironment, and in combination with other procedures.

The importance and significance of determining the pH of the wall of agiven hollow viscus organ has been recently dramatically magnified as aresult of the recent recognition that the pH of the wall of a givenorgan can be employed to accurately evaluate the vitality and/orstability of that organ as well as others; this is in contrast to merelydetermining whether such an organ is experiencing an ischemic event.Further, certain organs can be selected for monitoring, either alone orin combination, and evaluation of this organ or these organs can aid inpredicting the overall condition of the patient, or the onset of amultitude of pathologies, including predicting or identifying suchevents as multiple organ failure. Such a methodology can be employed togreatly enhance and supplement the monitoring of the critically ill, forexample.

It has also been observed that an unusually large negative bias isencountered when measuring the pCO₂ in saline with certain blood gasanalyzers (including those manufactured by Nova Biomedical, L.Eschweiler and Mallinckrodt) that have been standardized for blood butnot for saline. The presence or absence of unacceptable bias may bedetermined by the use of reference samples of tonometered saline. Theinter-instrumental bias encountered when measuring arterial blood gasesand especially pCO₂ in saline with different blood gas analyzersrequires that each institution derive its own normal values formeaningful use in clinical practice. It is reported that the precisionof the measurements made within a static environment may be improved andunacceptable interinstrumental bias eliminated, in whole or in part, byusing Gelofusine® (sterile 4% w/v succinylated gelatine in saline), aphosphate buffer, bicarbonate-buffered saline, or mixtures thereof.Unfortunately the diffusional characteristics may be altered, in whichcase the nomograms provided for the determination of steady-stateadjusted pCO₂ in saline cannot be used for the determination ofintramucosal pH with these fluids.

The time constant may be reduced to seconds by using an electrochemicalpCO₂ sensor directly in the lumen of the gut and measuring the pCO₂ ineither liquid or gaseous luminal contents, as described herein,Unfortunately, pCO₂ sensors are known for their tendency to drift andcannot be easily recalibrated in vivo.

In one aspect, the present invention provides a new apparatus and methodfor remotely sensing organ condition and conveying a signal, e.g. anelectrical current or optical signal, to an electronic or opticalapparatus located outside the organ under investigation. In oneembodiment, a transducer (or plurality of transducers) is attached to atonometric catheter for introduction into the organ along with thetonometric catheter. This first sensor generates and conveys a signalindicative of some desired aspect of organ condition, e.g., indicativeof the pCO₂, pH and/or PO₂ level of the organ or organ-wall. Forexample, in one preferred embodiment, mean ambient PCO₂, pH and/or PO₂of lumenal fluid or the like is measured or monitored via wire or othersuitable electromagnetic energy conveying means to an electronic circuitwhich interprets the electromagnetic signal and produces a report of theorgan condition. The electronic circuit may include an input forreceiving a separately determined signal indicative of the blood pH ofthe patient. Using this pCO₂, pH and/or pO₂ measurement along with blood(preferably arterial) pH data, the electronic circuit determines the pHof the organ wall under test and thereby provides information fordetermining the organ's current condition or perhaps predicting theorgan's future condition. The electronic circuit nay be suitablyconstructed from analog components, digital components or both.

In another embodiment, a pH, pCO₂ or PO₂ sensitive colorimetricsubstance is injected into an area adjacent to the organ, e.g., into thesampling chamber of the tonometric catheter, and an optical sensor isemployed to detect color change in order to determine the pH of the wallof that organ. The optical sensor can either be disposed in or on thetonometric catheter for introduction into the area adjacent the organ orit may be disposed outside the organ with fiber optic cable opticallycoupling the sensor to the tonometric catheter site at which the pHsensitive substance has been injected.

In another aspect the present invention provides a variety of new anddifferent tonometric catheter devices for sensing and/or sampling afluid or gas property (such as pH, pO₂, pCO₂, and the like) which isindicative of the condition of an internal organ, in conjunction orcombination with a walled catheter tube adapted for delivery or drainingfluids, such as nasogastric tubes, urinary catheters, uretericcatheters, intestinal feeding tubes, wound or abdominal drains (suctionor regular) and biliary tubes, or other catheters and stents, with orwithout remote sensing means for pH, pCO₂ and/or pO₂.

In still another aspect or embodiment, the device employs two separatewalled catheter tubes, one tonometric catheter tube for the measurementof a fluid or gas property, that is in communication with the samplingchamber; and a second walled catheter tube adapted for delivering ordraining fluids.

In yet another aspect or embodiment, the device employs a walledsampling chamber in communication with a sensing means, and a secondwalled catheter tube adapted for delivering or draining fluids.

Although not originally thought to be feasible or efficacious, thepresent invention in yet another embodiment has also accomplishedimproved accuracy and speed by the effective infrared sensor measurementof liquid or gaseous fluid parameters or compounds of interest, such aspCO₂, anesthetic gases, etc., admixed in a gaseous sampling medium,preferably air. This was previously not believed to be possible due tothe high gas volumes typically required for accurate infraredmeasurements, and because of erroneous measurements resulting fromincreased gas densities caused by higher tonometric sampling mediumpressures.

In view of all of the above, it will be appreciated that tonometricmethod can now be modified in a fashion that provides the advantages ofreduced equilibration time (with respect to saline) and without the needto recalibrate the sensor in vivo, or remove it for recalibration. Inthe improved method, and very generally, air is employed as the medium,and measurements can be taken either in discreet samples orcontinuously. The sampling medium air is aspirated from the walledsampling chamber of a tonometric catheter which has been inserted intothe organ of interest (e.g., the gut). The PCO₂ of the aspirated sampleis measured by employing a side-stream or main-stream, drift-free,non-dispersive infrared gas analyzer. The pCO₂ value obtained is thencompared with either (1) the arterial bicarbonate value and/or (2)another direct or indirect measurement or a "global" or "systemic"physiologic value (e.g., pH, pCO₂ or pO₂ of arterial, venous, umbilicalor capillary blood; mixed venous bicarbonate; arterial oxygen saturation(e.g., as measured by pulse oximetry); and-tidal pCO₂ ; transcutaneous(TCpCO₂) pCO₂) in order to make a determination of the condition of theorgan or if (A) a bicarbonate value must be obtained and/or (B) what, ifany, clinical therapy or intervention may be necessary or appropriatewith respect to oxygenation of the organ of interest.

In some embodiments, a Raman spectrometer may be employed, either inline or side stream, in place of the IR gas analyzer, as it will beappreciated by those skilled in the art that Raman spectroscopy offersdistinct advantages over the more direct infrared-type measurements incertain applications.

A preferred indirect measurement of a "global" or "systemic" pCO₂ valueis an end-tidal CO₂ value, or a transcutaneous CO₂ value

The present invention can successfully use a gaseous sampling medium,such as air, along with known commercially available non-dispersiveinfrared spectrophotometry devices, resulting in high sample andmeasurement reliability, faster equilibration, thus allowing for fasterand more frequent intermittent sampling or even continuous sampling,increased ease of use, and decreased sources of error, when compared tothe prior use of a liquid sampling medium (such as saline), and a bloodgas analyzer, for example.

Those skilled in the art will readily recognize the kind ofnon-dispersive, infrared gas analyzing devices contemplated by thepresent invention. Examples of these devices are those commerciallyavailable and marketed by such companies as Datex, Division ofInstrumentarium Corporation or Novametrix Medical Systems, Inc., forexample. Other examples of such devices and related equipment arediscussed and disclosed in U.S. Pat. Nos. 4,233,513; 4,423,739;4,480,190; 4,596,931; 4,859,858; 4,859,859; 4,907,166; 4,914,720;5,042,522; 5,067,492; 5,095,913, the disclosures and drawings of all ofwhich are hereby incorporated by reference herein.

Non-dispersive infrared gas analyzers in general are typicallymanufactured in either "side-stream" or "main-stream" configurations. Inone, a sample of a volume of gas is taken from a patient's gas flow(such as respiratory gas flow, a tonometric sampling chamber gas flow,or both) and conveyed through a sample tube to the infrared sensor andanalyzer; in such a device, the sample is not typically returned to thepatient's gas flow. The other common type is the so-called in-stream ormain-stream type, which has a sensor apparatus that mounts directlywithin the patient's gas flow conduit and senses and takes measurementsas the gas flows past the sensor.

In this regard, a tonometric apparatus according to the invention caninclude a temperature measurement feature, with a built-in thermistor,either in the catheter device or the sampling chamber itself, or in thesystem's processing instrumentation, to measure the sample temperatureas an indication of body core temperature and for purposes ofcalibrating or correcting pCO₂ (or other parameters) calculations. Sucha feature is especially desirable in systems using gas samples, due tothe volumetric responses of the gas to changes in temperature.

For further understanding of the invention, its objects and advantages,reference may be had to the following specification, the accompanyingdrawings, and the information incorporated herein by reference. Also,see our co-pending and commonly assigned applications Ser. No. 719,097,filed Jun. 20, 1991; Ser. No. 994,721, field Dec. 22, 1992; and Ser. No.014,624, filed Feb. 8, 1993, all of which are completely and expresslyincorporated herein by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view of a first embodiment of the tonometric catheter;

FIG. 2 is a partial view of a tonometric catheter similar to that ofFIG. 1, but having optional sensors mounted on the inside of thecatheter tube;

FIG. 3 illustrates the method of use of an exemplary tonometric catheterin measurement of the pCO₂ of the colon and also of the stomach, thespecific embodiment illustrated for colonic measurement being that ofFIG. 5 and the specific tonometric catheter for gastric measurementbeing that of FIG. 4;

FIG. 4 is another embodiment of the tonometric catheter with nasogastrictube;

FIG. 4A is a cross-sectional view of the tonometric catheter of FIG. 4taken substantially along the line 4A--4A of FIG. 4;

FIG. 4B is a cross-sectional view of the tonometric catheter of FIG. 4taken substantially along the line 4B--4B of FIG. 4;

FIG. 5 is yet another embodiment of the tonometric catheter havingmultiple sensing/sampling portions;

FIG. 5A is a cross-sectional view of the tonometric catheter of FIG. 5,taken substantially along the line 5A--5A of FIG. 5;

FIG. 6 is a detailed view illustrating the tonometric catheter of FIG. 4in use within the stomach;

FIG. 7 is a detailed view illustrating the tonometric catheter of FIG. 5In use within the colon;

FIG. 8 is a similar view illustrating the tonometric catheter of FIG. 1in use within the colon;

FIG. 9 is an electrical schematic diagram illustrating one embodiment ofelectronic circuit in accordance with the invention;

FIG. 10 is a view of one example of a tonometric catheter in combinationwith a urinary catheter;

FIG. 11 is a view of another embodiment of a tonometric catheter incombination with a urinary catheter;

FIG. 11A is a cross-sectional view of the tonometric catheter/urinarycatheter of FIG. 11, taken substantially along the line 11A--11A of FIG.11;

FIG. 12 illustrates one preferred example of the application of atonometric catheter device, with remote sensing and recordingapparatuses for monitoring and recording certain critical properties ofinterest;

FIG. 13A is a diagrammatic representation of an exemplary in-stream,non-dispersive infrared gas analyzer system usable in the presentinvention;

FIG. 13B is a diagrammatic representation of an exemplary side-stream,non-dispersive infrared gas analyzer system in the present invention;

FIG. 13C is a diagrammatic representation of an infrared sensorapparatus usable with the system of either FIG. 13A or FIG. 13B;

FIG. 14 is a schematic representation of a modified Raman systemaccording to the present invention;

FIG. 15 is a schematic representation of a number of alternatevariations on the invention;

FIG. 16 is a diagrammatic representation of a manual syringe, modifiedto provide to sample pressure equalization in the present invention;

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates a first embodiment of tonometric catheter 20. Thetonometric catheter comprises a length of suitable tubing 22, one end 32of which is closed, and the opposite end of which has a connector suchas a luer-lock 24. Luer-lock 24 is adapted to receive a complementaryfitting 26, which in turn couples through a second length of tubing 28to a three-way stopcock 30. Three-way stopcock 30 may be used toselectively connect tubing 28 to various sources of irrigation oraspiration. Other fittings can be used, depending on the particularapplication, including those wherein a tonometric catheter is used inconjunction with an infrared sensing device, a Raman spectroscopydevice, or the like.

Adjacent the closed end 32, tubing 22 is perforated as at 34. Aballoon-like tonometric catheter membrane 36 is fitted over the closedend so that the perforations 34 are enclosed, as illustrated. Thetonometric catheter membrane 30 has an internal sleeve diameter at 38which forms a tight fit with tubing 22. The preferred form of tonometriccatheter membrane is polydimethylsiloxane elastomer. The membrane may besealed to the tubing 22 with appropriate adhesive so that the tonometriccatheter membrane is sealed in a closed relationship to the outer wallof tubing 22, thereby forming a sampling chamber 40 adjacent closed end32. The tonometric catheter membrane has a certain elasticity to allowthe membrane to expand when filled with an aspirating fluid (liquid orgas).

The membrane 36 is preferably constructed such that at least a portionof it is selectively permeable to the liquid or gas fluid property ofinterest. In a preferred embodiment, it is selectively permeable tocarbon dioxide, and oxygen, so that pCO₂ and/or pO₂ can be measured. Itis also preferably impermeable to other materials that would interferewith the desired measurements, such as proteins and the like. In ahighly preferred embodiment, a gas permeable membrane is employed.

Bonded to either the inner wall (see FIG. 2) or the outer wall of tubing22 are one or more sensors 42 for detecting a property indicative ofpCO₂, PO₂ and/or temperature. Two such sensors are illustrated in FIG.1, bonded to the outside wall of tubing 22 with suitable adhesive. FIG.2 illustrates the sensor attached to the inner wall of tubing 22.

In a preferred embodiment, at least a portion of the tubing, but notnecessarily all of it, is made of a CO₂ impermeable material, such asthose based on polyurethanes, PVC's, or polyester elastomers derivedfrom the reaction of dimethylterephtalate 1,4-butanediol andα-hydro-Ω-hydroxypoly (oxytetramethylene). In preferred embodiments,this material can be PVC or polyurethane.

For purposes of sensing temperature, thermistor devices are presentlypreferred.

The sampling chamber 40 can be filled with an aspiration or samplingmedium (gaseous or liquid) that is used to absorb or otherwise provide ameans for incorporating and delivering or measuring the liquid orgaseous fluids of interest. Such a medium is selected depending uponmany factors, including the properties of the liquid or gaseous fluidsof interest, the type of sensor 42 employed, and the type of calibrationthat is necessary. Such mediums include air, bicarbonate solutions,bicarbonate-buffered solutions, phosphate-buffered solutions and salinesolution. It might be noted that gases often behave as fluids and aretherefore frequently considered to be fluids.

As noted above, when the sensor employed does not require frequentrecalibration, the need for the sampling chamber 40 to be incommunication with the proximate end of the tonometric catheter (thatremains outside the patient) may be eliminated since no aspiration isneeded. However, in many instances such communication may still bedesirable as aspiration may be required to calibrate the sensor orsensors, to replace the aspirating or sampling medium with a freshmedium, and to incorporate the gas or gases of interest.

Another embodiment of the tonometric catheter is illustrated in FIGS. 4,4A and 4B. As illustrated, the tonometric catheter can be appropriatelyconfigured to also serve as a nasogastric tube, either with or withoutan air lumen. With reference to FIG. 4, the tonometric catheter 20acomprises a multipassage tubing 62 which defines three individualpassageways or lumens, an optional air lumen 64, a suction lumen 66 anda tonometric catheter lumen 68. A tonometric catheter membrane, similarto that previously described, is attached at an intermediate location ontubing 62, allowing a portion of the tubing to extend beyond the end ofmembrane 36 to define the nasogastric tube 70, or a portion thereof.Tubing 62 is provided with a plurality of perforations 72 whichcommunicate between monometric catheter lumen 68 and the samplingchamber 40 defined by membrane 36. If desired, one or more sensors 42can be included in accordance with the above teachings, in which case asuitable conductor 56 may be routed through tonometric catheter lumen 68to exit at sealed aperture 58.

The nasogastric tube 70 is suitably provided with a plurality ofopenings 74 through which the stomach may be aspirated.

At the opposite end of tubing 62 the tubing splits to form threeseparate connections. Optional air lumen 64 communicates with optionalair lumen passageway 76, suction lumen connects with suction lumenpassageway 78 and tonometric catheter lumen 68 communicates withtonometric catheter lumen passageway 80. The tonometric catheter lumenpassageway is fitted with three-way stopcock 30, similar in function andpurpose to the three-way stopcock 30 described in connection withFIG. 1. If desired, a quick connect fitting 82 may be used to couple thesuction lumen passageway 78 with an aspiration source. As illustrated,the quick connect fitting preferably has angularly cut ends and aslightly enlarged midsection, making it easy to insert into the end ofpassageway 78 and also into the aspiration hose coupling (not shown).The enlarged midsection helps form a seal with the adjoiningpassageways. Preferably the quick connect fitting is fabricated ofdisposable plastic.

Yet another embodiment of the tonometric catheter is illustrated inFIGS. 5 and 5A. This embodiment is a multiple tonometric catheterembodiment employing a tubing 84 having a plurality of passageways orlumen as shown in the cross-sectional view of FIG. 5A. Specifically,tubing 84 includes an air lumen 86a which communicates with the endmostsampling chamber 36a and three additional tonometric catheter lumens86b, 86c and 86d, which communicate respectively with sampling chambers36b, 36c and 36d. As with the other embodiments, each sampling chambermay be provided with one or more sensors such as sensors 42. Aradiopaque turgsten plug 88 is positioned within each of the threetonometric catheter lumen 86b, 86c and 86d adjacent the distal end ofeach sampling chamber, serving to block the remainder of the tonometriccatheter lumen passageway and thereby ensuring that fluid pressureintroduced into each tonometric catheter lumen will cause the associatedsampling chamber to balloon outwardly as required during use. Similarly,a radiopaque tungsten rod 90 is fitted as a plug in the end of air lumen86a, serving to terminate the end of the air lumen passageway. Beingradiopaque, the tungsten plugs and tungsten rod aid in properlypositioning the tonometric catheters by being visible under fluoroscopeor x-ray. In addition, if desired, tubing 84 can be provided with aradiopaque stripe along all or part of its length.

At the proximal end at tubing 84 the luten 86a-86d diverge to definefour separate tubes 92a-92d. Each tube is fitted with a three-waystopcock similar to those described above. Each sampling connector mayoptionally be coded numerically by color, etc. While four approximatelyequally spaced sampling chambers have been illustrated in FIG. 5, itwill be understood that the invention can be modified to include agreater or fewer number of sampling chambers at different spacing asrequired for a particular application. It will also be understood thatsome or all of the sampling chambers can include one or more sensorscoupled to conductors 56, each preferably routed through thecorresponding lumen passageway.

Referring now to FIG. 9, a suitable electronic monitoring circuit willnow be described. In FIG. 9, a pCO₂ -sensitive CHEMFET semiconductordevice 46 has been shown schematically by the equivalent circuit modelenclosed in dotted lines. The device 46 thus comprises drain electrode150, source electrode 152 and reference electrode 154. The chemicallyselective system, such as a membrane system is depicted diagrammaticallyat 156. The substrate is grounded as at 158.

Source electrode 152 is coupled to an input lead of operationalamplifier 160 which includes feedback network diagrammatically depictedat 162. Operational amplifier 160 senses the drain source currentflowing through device 46 and converts this signal into a voltage signalwhich is output on lead 164. The drain source current changes inaccordance with changes in the chemical system under test. Morespecifically, as the pCO₂ level changes in the fluid exposed to device46, the drain source current changes accordingly. Hence the outputvoltage signal on lead 164 is likewise an indication of the pCO₂ levelof the organ under test. This voltage signal on lead 164 is coupled toan input of comparator 166 which also receives a reference voltageV_(ref), which may be supplied using a voltage divider network (notshown) or which may alternatively be provided by a digitally controlledvoltage source 168. The output of comparator 166 is fed to referenceelectrode 154 to provide a stable reference bias voltage. If a digitallycontrolled voltage source is used, this reference voltage can beadjusted and calibrated by a computer circuit yet to be discussed. Thevoltage signal on lead 164 is also fed to an analog to digital convertor170, which is in turn coupled to a microprocessor-based microcomputer172.

In order to automatically determine the pH of the wall of the hollowviscus organ under test, a separate gas analyzer sensor 174 is used todetermine the bicarbonate concentration in the arterial blood of thepatient. The output of sensor 174 is coupled through analog to digitalconvertor 176 to microcomputer 172. Microcomputer 172 is preprogrammedto determine or calculate the pH of the organ wall using the valuesprovided by analog to digital convertors 170 and 176. Conversion of pCO₂measurements can be converted into pH measurements automatically bymicrocomputer 172 using various equations and references disclosedherein or others well-known in the art.

Although many different types of output devices may be employed, stripchart recorder 178 and CRT monitor 180 have been illustrated. Stripchart recorder 178 and monitor 180 are coupled as output devices tomicrocomputer 172. Strip chart recorder 178 offers the advantage ofdeveloping an easily readable, permanent record of the fluctuations inorgan wall pH. Monitor 180 offers the advantage of providing digitalreadout of the pH value as well as displaying the upper and lowerexcursions of pH fluctuation. It desired, microcomputer 172 can beinstructed and/or preprogrammed using keyboard 182 to compare theinstantaneous pH value with doctor-selected upper and lower alarmlimits. If the measured instantaneous pH fluctuates outside thoselimits, microcomputer 172 can sound an alarm to alert hospital staff.

While a single semiconductor device 46 has been illustrated inconjunction with the electronic circuit of FIG. 9, the circuit may bereadily adapted for use with a plurality of semiconductor devices inorder to measure the pCO₂ at different locations substantiallysimultaneously. In such an embodiment, the data coming from each sensorcan be ted to a separate I/O port of microcomputer 172. In thealternative, a single I/O port can be used with the individual inputsignals being time multiplexed.

While some embodiments have been disclosed in connection with monitoringof the gastrointestinal tract and the urinary and ureteric tracts itwill be appreciated that its principles are applicable to other hollowinternal organs to monitor tissue or intramucosal pH, pCO₂, pO₂, etc.,and hence perfusion of those organs. Also while several detailedconstructions for tonometric catheters have been disclosed, it will beappreciated that other constructions may be developed which are equallysuitable. The disclosed constructions are presently preferred for thereason that they are readily fabricated using existing availablematerials. Other embodiments may include other, but equivalent materialsfor the tonometric catheter membrane and/or connective tubing. They mayalso differ in the specific fabrication details. As an example, thesampling chamber may be eccentric rather than symmetric about theconnective tubing.

As shown, for purposes of illustration, in FIG. 10, the tonometriccatheter device according to the present invention can be employed incombination with any number of different types of urinary cathetersknown to those skilled in the art. By such an arrangement, theconcentrations of CO₂, O₂ or other gases of interest, or otherparameters, can be determined and/or monitored, and traditional urinarycatheter operations can be performed, all with a single combinationdevice.

In FIG. 10, the membrane 536 is shown incorporated into a Foley-type,three-way balloon catheter, thus making the combination Foley-typeurinary and tonometric catheter a four-way catheter apparatus 520. Theexemplary combination urinary-tonometric catheter includes a tonometerlumen end 524 in fluid communication with a sample chamber 540, definedby the membrane 536, in a manner essentially the same as that describedabove in connection with FIG. 1 (with or without a temperature sensor).The four-way combination catheter apparatus 520 also includes thetraditional three-way Foley catheter components, such as a lumen end 525in communication with the Foley balloon 526, for purposes of ballooninflation, a lumen end 527 for drainage, and a lumen end 528 forinfusing irrigation solutions in order to prevent clot retention withinthe bladder, the applications and functions of all are familiar to thoseskilled in the art.

It should be noted that although the tonometric catheter arrangement ofFIG. 1 is shown in FIG. 10, merely for purposes of exemplaryillustration, in conjunction with a three-way Foley-type urinarycatheter, one skilled in the art will readily recognize that any of thetonometric catheter embodiments described and illustrated herein can beemployed in combination with such a Foley-type urinary catheter, as wellas with other familiar types of urinary catheters, such as a conical tipurethral catheter having a single eye, a Robinson urethral catheter, awhistle-lip urethral catheter, a Coude hollow olive-tip catheter,Macelot self-retaining four-wing or two-wing catheter, a Pezzerself-retaining drain, open-end head (used for cystotomy drainage), orany of a number of well-known urinary catheter types. See Urology 5thed., W. B. Sanders ed. Vol. 1, p. 512 (1986).

Another embodiment of the tonometric catheter is illustrated in FIGS. 11and 11A. As illustrated, the tonometric catheter is appropriatelyconfigured to also serve as a urinary or ureteric catheter, either withor without suction, which optionally employs sensors. With reference toFIGS. 11 and 11A, the tonometric catheter 220 comprises a multipassagetubing 262 which defines three individual noncommunicating (between eachother) passageways or lumens, an optional irrigation lumen 264, adrainage or suction lumen 266 and a tonometric catheter lumen 268. Atonometric catheter membrane, similar to that previously described, isattached at a distal location on tubing 262, allowing an intermediateportion of the tubing not extending beyond the end of membrane 236 todefine the uretary or ureteric catheter 270. Tubing 262 is provided witha plurality of perforations 272 which communicate between tonometriccatheter lumen 268 and the sampling chamber 240 defined by membrane 236.If desired, one or more sensors 242 can be included in accordance withthe above teachings, in which case a suitable conductor 256 may berouted through tonometric catheter lumen 268 to exit at sealed aperture258.

The urinary catheter or ureteric catheter portion 270 is suitablyprovided with a plurality of openings 274 through which the bladder orureters may be aspirated or irrigated.

At the opposite end of tubing 262 the tubing splits to form threeseparate connections. Irrigation lumen 264 optionally communicates withirrigation passageway 276, urinary lumen connects with suction ordrainage lumen passageway 278 and tonometric catheter lumen 268communicates with tonometric catheter lumen passageway 280. Thetonometric catheter lumen passageway is fitted with three-way stopcock230, similar in function and purpose to the three-way stopcock 30described in connection with FIG. 1. If desired, a quick connect fitting82 as seen in FIG. 4 may be used to couple the suction urinarypassageway 278 with an aspiration source. As illustrated, the quickconnect fitting preferably has angularly cut ends and a slightlyenlarged midsection, making it easy to insert into the end of passageway278 and also into the aspiration hose coupling (not shown). The enlargedmidsection helps form a seal with the adjoining passageways. Preferablythe quick connect fitting is fabricated of disposable plastic.

Yet another embodiment of the urinary catheter/tonometric cathetercombination illustrated in FIG. 11 and 11A may employ a multipletonometric catheter embodiment employing a tubing having a plurality ofpassageways or lumen as shown in the cross-sectional view of FIG. 5A.

In another embodiment of the present invention, a tonometric cathetermay be adopted to deliver a pharmaceutically-active agent, either forsystemic, local or topical activity, or a combination thereof. Forexample, an additional lumen, such as the irrigation/aspiration lumen264 shown in FIGS. 11 and 11A, may be used to deliver an active agent.In another embodiment, a portion of the device may be modified so as toprovide sustained release of the active agent of interest.

Thus, for example, the problems of nosocomial infection associated withcatheter insertion can be overcome by incorporating an antimicrobialagent into at least a portion of the polymeric material used tomanufacture the tonometric catheter, or by coating at least a portion ofthe device with a sustained release composition or bacteriostaticcoating, or by delivering the antimicrobial via the tonometric catheter.Such modifications are well known to those skilled in the art. See U.S.Pat. No. 4,677,143, incorporated herein by reference.

Classes of useful agents include bacteriostatic coatings, antimicrobialagents, nonsteroidal anti-inflammatory agents, topical anesthetics,topical vasodilators, metabolic suppressants, and other agents thatcould be delivered for absorption at the sites of the tonometriccatheter.

In still other embodiments, conventional gas analyzers may be employedexternally. A device such as that shown in FIG. 1 (or any of theexemplary catheter devices described herein) may be used in combinationwith a pump or aspiration means (not shown) for continuous or regularintermittent aspiration of a sample of the aspirating liquid or mediumthat is used to fill the sampling chamber 40. The sample removed by pumpor aspiration means via attachment to the luer-lock 24 can be optionallydesigned so that the sample aspirated at each sampling interval can bebrought in contact with an exterior, separate gas analyzing means orsensor (not shown) to determine the pO₂, PCO₂ and/or the like, of thesample. Such automatic sampling can be conducted employing a system asshown in FIG. 12. In the assembly a sampling system employs a personalcommuter to conduct evaluations and analysis of the samples withdrawnfrom the tonometric catheter 295.

Pump 203 is loaded with the sampling or aspirating medium, such assaline or air. Next, valve 201 is activated to withdraw a desired amountof the sampling fluid. The valve 201 is deactivated and pump 203 is usedto infuse the sampling chamber of the tonometric catheter 299 using acalibrated amount or, optionally, until a predetermined pressure issensed by a pressure transducer 215. The sampling fluid or medium isallowed to come to equilibrium with the wall of the organ or area ofinterest. Next the "dead space," i.e., the area of the lumen filled withthe sampling fluid that is not in equilibrium, is removed by activatingvalve 205, activating pump 207, activating valve 209 and infusing pump207; the waste 219 is discarded. A gaseous sample for analysis can thenbe withdrawn by deactivating valve 209, activating pump 207 to thendeliver the gaseous sample to an analyzer such as an infrared or a Ramangas analyzer (not shown) that provides data from the sample to the PC217, and the evaluation is conducted as described herein.

The sample gas analyzer or a separate gas analyzer may be optionallyemployed to determine the bicarbonate concentration in the arterialblood of the patient, as described above. Such option is depictedschematically in FIG. 12, wherein a blood gas analyzer or monitor 250 isprovided, with its data output signal being interfaced with theprocessing system 217. Such blood gas analyzer continuously monitors thepatient's intraarterial pCO₂, pH, pO₂, or other parameters of interestby way of a sensor, such as a fiberoptic sensor placed into thepatient's artery. Examples of commercial available blood gas analyzersand sensor components include those marketed by Puritan-Bennett (PB3300, see Lundsen, T. et al., J. Clin. Monit. 10:59-66 (1994), hereinincorporated by reference) or by Biomedical Sensors Ltd. (Pfizer)).

These systems (providing continuous arterial pCO₂, pH, and bicarbonatevalues) can also be interfaced into the tonometric pCO₂ systems usinginfrared or Raman spectroscopy technology (discussed herein) to providean actual value of intramucosal pH, as well as pCO₂ -gap and pH-gapmeasurements each time a tonometer pCO₂ or pO₂ measurement is taken,thus providing more timely trend values for these parameters. Thisgreatly facilitates interpretation of these measurements, since regional(tonometer pCO₂ and intramucosal pH) and systemic (arterial pCO₂ and pH)can be compared rapidly and directly. It should further be noted thatsuch an optional blood gas monitoring/analyzing interface can beadvantageously employed whether liquid or gaseous tonometric sampling isused.

It has also been discovered that the pH of venous blood provides anexcellent measure of the adequacy of tissue oxygenation of the wholebody or organs, including solid organs, comparable to that achieved inhollow viscus organs by the method described herein, as well as thatdescribed in the above-mentioned, commonly-assigned applications thatrelate to the use of a tonometric catheter to determine the adequacy oftissue oxygenation via the measurement of the pH of the wall of ahollow, viscus organ.

In numerous clinical settings it is now common to monitor the carbondioxide concentration of the arterial blood of patients, particularlythose who are critically ill or under anesthesia; this measurement hasbeen determined to bear a usually predictable relationship tointramucosal pH. One of the most common non-invasive techniques formeasuring arterial CO₂ is doing so indirectly by measuring the CO₂concentration of the last gas expired from a patient (so called"end-tidal") during normal respiration. The arterial CO₂ concentrationis then calculated by employing the known correlation between theend-tidal pCO₂ and pCO₂ of the arterial blood.

It has been discovered in another aspect of the present invention thatend-tidal CO₂ (as well as the underlying correlation between end-tidalCO₂ and the pCO₂ of arterial blood) may also be useful in makingclinical determination of the condition of an organ of interest when theend-tidal CO₂ is compared and contrasted with the pCO₂ of air aspiratedfrom a tonometric catheter having a walled sampling chamber insertedinto an organ of interest. These measurements having the addedconvenience of both being measurable by IR or Raman gas analyzers.

However, in order to fully appreciate this, a detailed understanding ofthe general tonometric method is useful. This background is helpfulprimarily for the skilled artisan to fully appreciate the relationshipof moving from the general tonometric method (which employs pCO₂associated with the wall of the organ of interest and the bicarbonateconcentrations of arterial blood) to even more indirect but usefulmeasurements.

In accordance with one preferred embodiment of the present invention,the condition of an organ of interest is determined in a patient in needof such determination when the pCO₂ associated with the wall of theorgan of interest is sampled and compared to substantiallycontemporaneous arterial or venous pCO₂ values or, in a highly preferredembodiment, end-tidal pCO₂ value(s); the pCO₂ of the wall of the organmay also be compared to: venous or arterial pCO₂ or pH; mixed venousbicarbonate values; transcutaneous pCO₂ ; arterial oxygenation(saturation), arterial pO₂, umbilical blood gases, capillary bloodgases, and the like.

While not intending to be bound by theory, the following is offered toput these aspects and embodiments of the present invention in propercontext.

The assumptions upon which the indirect measurement of intramucosal pH(pHi) are based are valid in normally perfused tissues. In thesecircumstances, the indirect measurement of intramucosal pH is identicalto that measured directly in the submucosal space with a microprobe.

The indirect measurement of intramucosal pH falls in parallel with thepH made directly in the submucosal space when an intramucosal acidosisis induced by endotoxemia, low-flow or no-flow. In those circumstancesin which the intramucosal acidosis in induced by endotoxin and flow tothe gut is maintained at control levels the measurements are in closeagreement (r=0.945). When induced by low-flow and especially no-flow theindirect measurements underestimate the severity of acidosis present inthe submucosal space. The disparity between indirect and directmeasurements observed in low-flow and no-flow states disappears whenblood flow is reestablished and the pH is allowed to return towardsnormality. Inspection of the twenty-minute values obtained in Antonssonet al's study reveals that the degree of dissociation observed betweenindirect and direct measurements is a linear function of the rate ofchange in intramucosal pH induced.

An additional primary assumption upon which the validity of thetonometric measurement of the adequacy of tissue oxygenation is that thebicarbonate concentration in tissue fluid is the same as that beingdelivered to it in arterial blood. It has been postulated that thedissociation between calculated and measured pH in low-flow andespecially no-flow states may be due to a dissociation between arterialand interstitial bicarbonate induced by the buffering of metabolic acidsby tissue bicarbonate.

The hypothesis does not account for the law of mass action whichdictates that the fall in bicarbonate concentration induced by theaddition of a fixed acid load to a "closed system" from which CO₂ cannotescape, such as the extracellular fluid compartment, is inhibited by theaccumulation of CO₂. The addition of even large amounts of fixed acid toa "closed system" does not produce a significant reduction inbicarbonate concentration but does produce a significant rise in pCO₂. Afall in bicarbonate occurs only when venous blood enters the pulmonarycirculation, an "open system" from which the CO₂ added to the venousblood by the buffering of the fixed acid load in the dysoxic tissue bedis able to escape. The fall in arterial bicarbonate thus induced causesthe tissue bicarbonate to fall by equilibration with the loweredbicarbonate concentration in arterial blood returning to the tissue bed.The fall in arterial bicarbonate induced by the escape of CO₂ from thelungs cannot cause a reduction in tissue bicarbonate concentration in ano-flow state for it is unable to enter the tissue bed.

The tissue bicarbonate should be the same as that in arterialbicarbonate perfusing the tissue bed in all circumstances except perhapsvery transiently after a sudden and large change in arterial bicarbonateinduced by an intravenous bolus of bicarbonate or sudden change inpulmonary ventilation.

As a precaution, however, it is wise to wait until the arterialbicarbonate has been stable for some 10 to 15 or better yet 30 minutesbefore measuring the intramucosal pH after an intravenous bolusbicarbonate or sudden changes in ventilation regimes.

It is therefore suggested that the primary assumption upon whichtonometric measurement of intramucosal pH is based, namely that thetissue bicarbonate is the same as that in arterial blood, is valid inmany relevant clinical settings, including those in which thedissociation between measured and calculated intramucosal pH wasgreatest. The indirect measurement of intramucosal pH appears to be anaccurate measure of the pH in interstitial fluid in the most superficiallayers of the intestinal mucosa especially in those circumstances inwhich the measurement is of greatest value, namely patients who appearby all conventional criteria to be adequately resuscitated. The onlycircumstance in which the measurement might be inaccurate for anextended period is a no-flow state. In this circumstance, the indirectmeasurement is so abnormal that the presence of the intramucosalacidosis should not be missed even if there is a large discrepancybetween actual and assumed measurements. Transient inaccuracies may beexpected following an intravenous bolus of bicarbonate or sudden changein pulmonary ventilation.

STOICHIOMETRIC ANALYSIS OF DETERMINANTS OF TISSUE ACIDOSIS

During aerobic metabolism the pH of tissue fluid is determined by thebicarbonate concentration in tissue fluid, the CO₂ released by oxidativephosphorylation, and the balance between ATP hydrolysis and resynthesis.In gastric glands the intracellular pH is the same as the extracellularpH in acidotic states. The pH of the extracellular fluid (ECF) isdetermined by the amount of metabolic acid present and the ability ofthe ECF to buffer the acid. The pCO₂ attained following the buffering ofa volatile (H₂ CO₃ from oxidative phosphorylation) or fixed acid load(protons from ATP hydrolysis) in a closed system, such as the ECF, maybe calculated in the manner described by Cattinoni and Feriani.

In normoxic tissues 6 mmol of CO₂ are produced for every mmol of glucoseconsumed in the generation of 38 mmol ATP. 13.5% of a volatile carbonicacid load added to ECF remains after being buffered by proteins anddetermines the pCO₂ present in the ECF. Assuming that the bicarbonateconcentration in ECF is 25 mEq/1 the metabolism of one mM glucose givesrise to a pCO₂ of 27 mmHg (6×0.135/0.03). In normoxic and restinghealthy subjects with a tissue bicarbonate of 25 mEg/1 the pCO₂,determined tonometrically, is 40 mmHg and the intramucosal pH 7.40. Ifit is assumed that the protons released by ATP hydrolysis are exactlybalanced by the protons consumed by ATP resynthesis in oxidativephosphorylation then the aerobic metabolism of 1.48 mM glucose isrequired to generate the volatile carbonic acid necessary to attain thepCO₂ of 40 mmHg (27×1.48=40 mmHg) and pH of 7.40 found in normoxic ECFwhen the tissue bicarbonate concentration is 25 mEq/1.

The pCO₂ attained from the buffering of the volatile acids released intonormoxic ECF in a tissue bed should increase as the metabolic rateincreases, the increased demand for oxygen in the absence ofreplenishment by flowing blood being met exclusively by an increase inoxygen extraction ratio. A rise in metabolic rate of the magnitude seenin an exercising athlete, which may be as great as 900%, can be expectedto cause a rise in equilibrium pCO₂ and hence fall in intramucosal pH innormoxic tissues. The magnitude of the fall in pH induced by the rise inpCO₂ is offset by the rise in tissue bicarbonate also induced by thebuffering of carbonic acid (a volatile acid). The rise in metabolic rateobserved in the critically ill is a fraction of that seen in anexercising athlete. Furthermore the oxygen extraction ratio is unchangedand more often decreased in septic patients who exhibit the highestmetabolic rate in the critically ill. In any event, the increasedmetabolic demand for oxygen in the critically ill, especially in thosewho are septic, is primarily met by an increase in oxygen delivery,oxygen delivery being "demand-dependent" in these circumstances. ThepCO₂ attained by the buffering of the volatile acid load generated innormoxic ECF should not, therefore, be significantly influenced bychanges in metabolic rate of the order encountered in the criticallyill.

Aerobic glycolysis and associated generation of CO₂ by oxidativephosphorylation decreases in dysoxic states as the availability ofoxygen relative to demand decreases. Thus the fall in tissue pH inseverely dysoxic states is due almost exclusively to the protonsreleased by adenine nucleotide hydrolysis and their interaction with thebody buffers.

If it is assumed that the intramucosal pCO₂ and pH are solely determinedby the amount of volatile and fixed metabolic acid being buffered in theECF at the time, the intramucosal pH can be expected to remain constantas oxygen delivery is reduced with or without a reduction in blood flowuntil the point at which supply-dependency or dysoxia develelops. Belowthis point the pCO₂ in ECF should rise and the intramucosal pH fall asthe contributions by aerobic metabolism to volatile acid decreases andby anaerobic metabolism to proton release increases with furtherreductions in oxygen delivery.

Intramucosal pH

The buffering of the protons by tissue bicarbonate in dysoxic statescauses the pCO₂ to rise. As the bicarbonate concentrations in a "closedsystem", such as the ECF, is not significantly reduced by the additionof a fixed acid load, the fall in pH must be inversely related to therise in log pCO₂ at any given concentration of tissue bicarbonate. Theconstant bicarbonate line at 25 mEq/1 on a pH-log pCO₂ diagram will showthat the pCO₂ in normoxic ECF at a point A to be 40 mmHg and the pH tobe 7.40. The bicarbonate line moves to the right as the equilibrium pCO₂rises above 40 mmHg to a point B in dysoxic states and the tissue pHfalls below 7.40. The pH in the dysoxic state may be determined byextrapolation from the pCO₂ intercept on the constant bicarbonate lineat 25 mEq/1.

The fall in pH induced by dysoxia alone in a tissue with a knownbicarbonate concentration may be computed from the difference betweenthe pH in the normoxic and dysoxic states determined from the sameconstant bicarbonate line (pH-gap), log of the ratio p₁ CO₂ /p_(a) CO₂(B-A) or their antilog equivalents (pCO₂ -gap and H⁺ -gap) . It will beappreciated that pCO₂ -gap is defined as pCO₂ -gap=P₁ CO₂ -p_(a) CO₂,and H⁺ -gap=H_(a) ⁺ -H₁ ⁺. These determinations of the magnitude in fallin pH induced by dysoxia are all dependent upon the assumption that thebicarbonate concentration in the dysoxic ECF is the same as that presentin normoxic ECF. If it is assumed that the pCO₂ in normoxic ECF is thesame as that in arterial blood (p_(a) CO₂) and the tissue pCO₂ indysoxic ECF is the same as the intramucosal pCO₂ measured from the lumenof the gut with a walled sampling chamber tonometer (p₁ CO₂) then theactual pH in dysoxic ECF may be calculated from the following formula(with pH_(a) =pH of arterial blood):

    Intramucosal pH=pH.sub.a -(log p.sub.1 CO.sub.2 -log p.sub.a CO.sub.2) =pH.sub.a -log p.sub.1 CO.sub.2 /p.sub.a CO.sub.2

and displayed in a perceptible form, such as human readable or audibleform, or machine readable form. Thus, by relating the differencesbetween measured values, wherein the term "difference" does notnecessarily mean an arithmetic difference, but refers generally to acomparison of measurements, for example by employing functions andformulas, important biological information may he obtained.

CLINICAL IMPLICATIONS

The indirect measurement of intramucosal pH provides an accuratediagnostic test for the presence of macroscopic and clinical evidence ofgastric, small intestinal and large intestinal ischemia in patients. Thesensitivity of the intramucosal pH as a diagnostic test for gastricischemia in man is reported to be 95% and the specificity 100%. Forsevere ischemic colitis after abdominal aortic surgery the sensitivityis reported to be 100% and the specificity 87%. Of particular relevanceto patients who are critically ill is the inability of those with anintramucosal acidosis to secrete acid in response to pentagastrin. Thosepatients who have a normal gastric intramucosal pH secrete acid inresponse to this stimulus. It has been suggested that the inability tosecrete acid in patients with an intramucosal acidosis may be due to anenergy deficit secondary to a dysoxic state. An energy deficit is aknown cause of stress ulceration in animals and an impairment of gastricmucosal oxygenation the likely cause of stress ulceration in patients.

The gastric intramucosal pH, measured following the administration of anH₂ -receptor antagonist to avoid confounding influence of the backdiffusion of acid and/or CO₂, is inversely related to the hepatic venouslactate concentrations in patients having cardiac surgery (r=-0.71) andcorrelates closely with this and other indices of splanchnic tissueoxygenation (r=0.92). The gastric intramucosal pH provides, therefore,an index of the adequacy of splanchnic tissue oxygenation.

The gastric intramucosal pH correlates very well and inversely withsystemic blood lactate when it is abnormally elevated. In manycircumstances, however, blood lactate is normal when the intramucosal pHis low and no correlation between the variables can be demonstrated.Indeed a fall in gastric intramucosal pH may precede a rise in bloodlactate in a deteriorating patient by many hours or even days. Changesin intramucosal pH influence the pH dependent enzymes regulating carriermediated afflux of lactate from muscle and the pH dependent enzymephosphofructokinase which regulates the rate of anaerobic glycolysis. Inaddition blood lactate Is the net effect of both production by anaerobicglycolysis and consumption by tissues such as the myocardium. Theoverall correlation between the two variables is thus rather poor(r=-0.40) but nevertheless statistically significant (p=-0.026). Thus inaddition to providing indices of gastric mucosal and splanchic tissueoxygenation the indirect measurement of gastric intramucosal pH providesan index of the adequacy of global tissue oxygenation.

The indirect measurement of intramucosal pH provides a measure of theadequacy of tissue oxygenation in the most superficial layer of themucosa, a region of the gut rendered relatively hypoxic by the countercurrent exchange system within the mucosal vasculature and henceespecially sensitive to alterations in the adequacy of tissueoxygenation. It also provides a measure of the adequacy of tissueoxygenation in a region of the body that is among the first to developan inadequacy of tissue oxygenation or dysoxia in shock and the last tobe restored to normality with resuscitation. Splanchnic vasculature isselectively constricted by the endogenous vasoconstrictors released inshock. For these reasons a fall in intramucosal pH may occur hours todays in advance of any other conventional evidence of an inadequacy oftissue oxygenation, most specifically arterial acidosis, elevation inblood lactate, hypotension and oliguria.

It is concluded that the indirect measurement of gastric intramucosal pHprovides a sensitive measure of the adequacy of splanchnic and evenglobal tissue oxygenation in patients in addition to providing an indexof the adequacy of superficial gastric mucosal oxygenation.

Correlations with acid-base balance and clinical events

The indirect measurement of gastric intramucosal pH may correlate veryclosely with the arterial pH (r=0.67) and other systemic indices of adisturbance in acid-base balance such as arterial bicarbonate (r=0.50),the base deficit in extracellular fluid (r=0.60) and base deficit inblood (r=0.63) . This is consistent with the deduction that gastricintramucosal pH provides an index of the balance between the protonsreleased by ATP hydrolysis and consumed in the resynthesis of ATP byoxidative phosphorylation. As with global measurements of blood lactatechanges in systemic acid-base balance provide a very dampened signal ofdisturbances in the adequacy of tissue oxygenation. A fall inintramucosal pH will often precede a fall in arterial pH by hours oreven days.

The predictive value of measurements of gastric intramucosal pH foroutcome are superior to those of the systemic measures of acid-basebalance. Maynard et al, for example, compared the predictive value ofmeasurement of gastric intramucosal pH with those of arterial pH andbase excess for death in ICU patients. The likelihood ratio forintramucosal pH was 2.32, for arterial pH 1.52 and base excess 1.47.Logistic regression showed only intramucosal pH to independently predictoutcome. In Boyd et al's study, the gastric intramucosal pH was likewiseof better predictive value for outcome than base excess. Clinicalexperience has shown that changes in gastric intramucosal pH correlatefar better with the passage of clinical events than either the arterialpH or base excess. Indeed abnormalities in these systemic measures ofacid-base imbalance will often occur only as the intramucosal acidosisis being reversed and the patient's condition is improving.

Reperfusion after the low-flow and particularly no-flow states inducedin Antonsson et al's validation study in pigs caused the intramucosal pHto rise and the arterial bicarbonate to fall. Similarly in patients thereversal of a severe intramucosal acidosis may be accompanied by a fallin arterial pH and base excess of abnormally low levels. Theseobservations are consistent with the consequences described above ofreestablishing perfusion in a dysoxic tissue bed in patients. The pCO₂in the venous effluent leaving the dysoxic tissue bed is elevated butthe bicarbonate concentration is not significantly reduced by thebuffering of the fixed acid in the tissue bed. The bicarbonate is onlyreduced by the loss of CO₂ during the passage of the venous effluentthrough the pulmonary circulation (an open system). As dissociationbetween the direction of change in the intramucosal and systemic pH isto be expected after flow is reestablished through a dysoxic tissue bed.

Intramucosal pH as a therapeutic target

"Gut-directed" and "intramucosal pH-directed" therapies may improveoutcome. These therapies use a normal intramucosal pH or intramucosal pHgreater than 7.35 as an additional therapeutic goal in the resuscitationof patients. This pH was chosen to ensure the pH was maintained wellwithin the normal limits reported for normal subjects. The normal limitsmay, however, differ from institution to institution with the use ofsaline and different blood gas analyzers, a problem solved by the airsampling medium (IR or Raman pCO₂) analysis embodiments of the presentinvention. It is furthermore possible that an end-point other than 7.35might be more appropriate. Values such as 7.25; 7.30; 7.35; 7.37 etc.may also be useful.

While it is clearly desirable to maintain a normoxic state bymaintaining the pH-gap at zero, it is not necessarily desirable tomaintain the pHi at normal levels. There is a considerable body ofevidence indicating that mild degrees of cellular acidosis protect cellsin anoxia and ischemia possibly by limiting the activity of theautolytic enzymes responsible for cell injury and death. A cellularacidosis may in addition facilitate carrier-mediated afflux of lactatefrom cells and bring the intracellular pH to an optimal range foranaerobic glycolysis during anaerobic metabolism. Furthermore theaddition of bicarbonate to the extracellular environment attenuates thefall in intracellular pH during ATP depletion and accelerates celldeath. The presence of an actual intramucosal acidosis may, therefore,be desirable and efforts to correct a metabolic acidosis withbicarbonate potentially harmful. Indeed the practice of correcting ametabolic acidosis induced by a cardiac arrest by the administration ofbicarbonate is no longer recommended.

It is concluded that acid-base balance is intimately related to theadequacy of tissue oxygenation in so far as it relates to the balancebetween the protons released by ATP hydrolysis and consumed by ATPsynthesis from oxidative phosphorylation. The intramucosal pH isdetermined by the pCO₂ attained following and buffering of the metabolicacid released into the ECF and the bicarbonate concentration in ECF atthe time--the "buffer hypothesis". The intramucosal pH is related toblood flow only in so far as it relates to the adequacy of tissueoxygenation. The assumption that tissue bicarbonate is the same as thatin arterial bicarbonate is only valid in the absence of the generationof an alkaline tide and associated secretion of acid. The indirectmeasurement of gastric intramucosal pH is the sum of the effects ofseveral determinants of an intramucosal acidosis. It is relevant toactivity of pH-dependent enzymes especially as they might relate tocellular injury in dysoxic states. By eliminating the confoundingeffects of disturbances in systemic acid-base balance the pH-gapprovides a measure of the acidosis attributable to an imbalance betweenATP hydrolysis and resynthesis, or degree of dysoxia present. Systemicmeasures of acid-base balance may be dissociated from the adequacy oftissue oxygenation upon reperfusion of a dysoxic tissue bed andcorrelate poorly with clinical events relative to the measurement ofgastric intramucosal pH.

In light of all the above, it will be appreciated that one series ofembodiments of the present methods relate to the use of arterial carbondioxide concentrations (measured directly or indirectly, preferably asan end-tidal carbon dioxide value) as a predictive indicator of the pHof the most superficial layer of the mucosa of the wall of an internalsolid organ, particularly the gut. In recognizing that ##EQU1## and thatp_(a) CO₂ is approximately equal to pCO_(2-end) tidal, thus ##EQU2##Either or both of these may be employed.

In accordance with the practice of the methods of the present inventionsthe pCO₂ of the wall of the organ is determined. This is preferably doneby inserting a tonometric catheter with a walled sampling chamber intoor adjacent the organ of interest. The sampling chamber is filled with agaseous or liquid sampling medium such as air or saline. The samplingmedium is allowed to come to equilibrium (equilibrate) with the area sothat the pCO₂ concentration of the sampling medium reflects the pCO₂ ofthe superficial layer of the mucosa of the organ of interest. The pCO₂concentration of the sampling medium is determined, giving p₁ CO₂.

In conjunction with the determination of the pCO₂ of the mucosa, thecarbon dioxide concentration in arterial (p_(a) CO₂) or venous blood isdetermined directly or indirectly. (A highly preferred indirect measureis end-tidal pCO₂, or pCO_(2-end) tidal). The two values (e.g., p_(a)CO₂ and p₁ CO₂) are then subjected to a nomogram, such as thosedescribed in equations above, to determine for example, a pHi value orpH-gap. The time integrated pH-gap can be used as a parameter forassessing the cumulative effects of tissue damage over time. The timedifferentiated P₁ CO₂ can be used as a parameter to determine the rateand direction of change in P₁ CO₂ which may be useful in situations whenP₁ CO₂ may change rapidly (e.g. ventilation changes during ventilatorweaning).

In a highly preferred embodiment, the sampling medium for the walledsampling chamber is air. The air is aspirated to an IR or Ramanspectrometer. In combination, the measurement of end-tidal pCO₂ isemployed as a substitute for the arterial p_(a) CO₂. The end-tidalrespiratory air is likewise aspirated to an IR or Raman spectrometer.Both gas analyzing devices are controlled by a microcomputer, which alsoaffects the selected nomogram or nomograms which compare the pCO₂ of thewall of the organ (gut) with the end-tidal pCO₂ value. The gas analyzingdevices may operate on a single channel, or via multiple channels.

Additional detection techniques may be performed on the air aspiratedfrom the patient, either via respiration or from the tonometric walledsampling chamber. For example, IR or Raman analyses may be performed todetermine the level of anesthetic gases, such as N₂ O. The results ofthe nomogram are displayed on a monitor (not shown) in human or machinereadable form.

In a highly preferred embodiment, the operation of one example of aninfrared gas analyzer is controlled by a microcomputer. Themicrocomputer itself is not, by itself, part of the present invention.For this reason and because one skilled in the relevant arts couldroutinely program a general purpose computer to follow the routinesrequired for this application, the microcomputer will not be describedin detail herein. (See the U.S. patents incorporated herein byreference.)

Referring now to FIG. 13A, a gas analyzer or detector 320a is shown inaccord with the principles of the present invention. Analyzer 320a isspecifically designed to monitor the concentration of carbon dioxide inthe exhalations of a medical patient--e.g., a patient being ventilatedduring a surgical procedure.

The major components of the infrared gas analyzer 320a are a poweredunit 322a and a sensor assembly 324a of a transducer head 326a and anairway adapter 328a. The transducer head 326a is connected to the unit322a of the gas analyzer 320a by a conventional electrical cable 330a.

In the application of the invention depicted in FIG. 13A, the gasanalyzer 320a is employed to measure fluid parameters of interest,similar to the apparatuses shown and discussed above, except that agaseous sampling medium, such as air, is conveyed, either manually orautomatically, as shown above, and analyzed by the infrared sensorassembly 324a, where the sampling medium is conveyed to the assembly324a via one of the above described tonometric catheter devices. Thisinformation can be effectively employed by medical personnel to monitorthe condition of a patient's internal organ more accurately and morequickly than before.

FIG. 13A depicts an in-stream type of infrared gas analyzer, shownmerely for purposes of illustration, but one skilled in the art willappreciate that the same principles apply to the use of a side-streamtype IR gas analyzer, such as that shown in FIG. 13B.

FIG. 13B depicts a side-stream infrared gas analyzer, similar to that ofFIG. 13A, except that the infrared sensor is located inside the poweredunit 322b. Also, sampling line 331b is used to convey a continuousgaseous sample from the patient by way of an airway adapter 333b. Thegaseous sample is conveyed from the sampling line 331b through a watertrap 335b (in order to remove condensate) to the sensor located in thepowered unit 322b.

FIG. 13C schematically depicts an infrared sensor, which can be used inthe infrared sensor assembly 324a of FIG. 13A, or in the powered unit322b of FIG. 13B. In FIG. 13C, an infrared light source 337c directs aninfrared beam through a gas sample cell 339c (located in sensor assembly324a of FIG. 13A, or in powered unit 322b of FIG. 13B), which containsthe gas sample, to a detector 341c, which directs its output signal to asignal processor 343c.

It will be appreciated that Raman spectrometers (gas analyzers) offeradvantages over IR analyzers and may be employed in the presentinvention. A Raman spectrometer is outlined and discussed in Westenskow,D. R., et al., Anesthesiology 70:350-355 (1989) and Westenskow, D. R. etal., Biomed. Inst. & Technol. November/December:485-489 (1989), hereinincorporated by reference. It will also be appreciated that amultichannel Raman in combination with multiple catheters is alsocontemplated by the present invention. See Niemczyk, T. M. et al., LaserFocus World March:85-98 (1993), herein incorporated by reference. Theuse of the combination of a tonometric catheter and a Raman spectrometerallow the measurement of oxygen gas; nitrogen gas; water; N₂ O and otheranesthetic agents such as halothane, enflurane, isoflurane andsevoflurane, all of which exhibit Raman scattering. Raman devices notonly measure pCO₂ more accurately, but can measure N₂, O₂ and H₂ Odirectly. This may reduce the potential error associated with certain IRtechniques, especially where other substances (N₂ O; O₂ ; H₂ O) mayeffect the IR pCO₂, measurement due to errors from overlappingwavelengths. The ability to measure O₂ directly with a Raman systeminstead of employing two sensors to measure O₂ and CO₂ as with the IRsystem is also important, especially with tonometric samples wherein thevolume of sample may not be sufficient for two measurements.

By measuring O₂ and N₂, air leaks may be detected and detection ishighly accurate. For example, equilibrated tonometric samples could becompared to the air concentration of O₂ and N₂. Any samples that "looklike air" to the system would thus be discarded. This may be especiallyuseful in situations where a pCO₂ in the stomach is high (e.g. 80 mmHg)and mixing with air during high suction from a nasogastric tube mayreduce the CO₂ level, but not to zero. In a Raman system, this samplewould be detected as an air leak. However, in an IR system an inaccuratepCO₂ reading may result because the means for detecting the air leak arebased primarily on the pCO₂ reading.

Another important advantage of the Raman spectrometer is the ability toemploy a fiberoptic probe within the sampling chamber 40 of thetonometric catheter. The fiber optic probe may also be used incombination with the catheter such that the tip of the fiberoptic proberesides inside the balloon of the catheter. This approach allows low orno dead space applications and lends itself to applications whereexcessive inflation of the balloon is not possible or desirable e.g.colon or stomach of a neonate, within a wound and on surfaces of organs.

The sampling principles used with the Raman spectrometers are similar tothose used with side-stream monitors, discussed above, in that a sampleis aspirated from the patients respiratory line and analyzed. Thus, toconnect a tonometric catheter of the present invention to the Ramanspectrometer, a pump to infuse and aspirate the sample may be added.Alternatively, the aspirating pump on the Raman spectrometer may bemodified in a manner to allow it to infuse the tonometer balloon(intermittently or continuously), alone with its normal function ofaspirating samples for respiratory and anesthetic gas measurements. Thismodified system is shown in FIG. 14.

As shown in FIG. 14, a Raman spectrometer may contain a gas sample cell416 between a light source 422 such as a laser, and an output mirror424. The Raman scattered light is directed through detection means suchas collection optics, filters, focusing optics and detectors, known tothose skilled in the art, are depicted collectively at 426 in FIG. 14. Amicroprocessor and display are generally referred to at 428.

Also shown in FIG. 14, in a preferred system of the present inventionemploying a Raman spectrometer, a aspiration and infusion pump 430 is incommunication with a pump switch valve 434 which controls the incomingand outgoing sample in the sample cell 416. A sample from a tonometricballoon enters the system as shown at 410 and, as shown at 412, arespiratory sample may also enter the system. Both samples then enter atonometer/respiratory valve 414 that allows either one of the samples toenter the sample cell 416 while excluding the other sample. The samplecell of the Raman spectrometer may be on the order of 5 microliters,much smaller than the 800 microliter cell of a typical IR system, and istherefore easily able to accurately measure even a low volume tonometricsample.

A preferred Raman spectrometer employed in the present invention is theRascal® II, available from Ohmeda Monitoring Systems, Louisville, Colo.The Rascal® II incorporates a feature that continuously flushes thesample cell with room air to keep the optics of the sample cell clean.Because respiratory gases are continuously sampled at a rate of about200 ml/min, the typical air flush rate of about 5 ml/min does not impactthe accuracy of the measurement. In contrast, a tonometer sample flowmay be slower and the sample volume is less and therefore the air flushmay impact the accuracy of the measurement. Thus, in a preferredembodiment, this air flush feature may be modified as shown in FIG. 14,to contain an automatic air intake valve 418 wherein the flow ofincoming room air may be controlled. The automated air intake valve 418is in communication with the tonometric/respiratory valve 414 generallythrough a control interlock (depicted with dashed line) known to thoseskilled in the art, wherein the is automated air intake valve 418 willbe open when a respiratory sample is flowing through thetonometer/respiratory valve 414, and closed when a tonometric sample isflowing through the valve 414.

It will also be appreciated that with improvements in solid statetechnology, a laser system may be designed to utilize a Ramanspectrometer in a mainstream system. Furthermore, improvements in laserscience will result in smaller size lasers and less noise, cost andpower consumption.

FIG. 15 schematically illustrates a biological filter (biofilter)apparatus 340 being employed in-line, between an exemplary tonometriccatheter apparatus 342 and the above-discussed exemplary infrared orRaman sensor assembly 324 for filtering out undesirable contaminants.The bio-filter 340 can be any of a number of biological filters known tothose skilled in the art and is especially useful to allow side-streamsystems to allow sample return or in-stream infrared gas analyzerapparatuses to be used in multi-patient applications. An example of asuitable biofilter for this purpose is a Dualex™ 0.2 micron filter unit,SLFG 025 XS, manufactured by Millipore Corporation, Bedford, Mass.

Due to the sensitivity of the current commercial infrared sensors ordetectors to moisture content, and due to the high moisture content ofair sampling-medium based pCO₂ samples coming from both an in vivotonometric walled sampling chamber and end-tidal samples, a moisturefilter or other dehumidifying means is optionally employed. For example,an air-based PCO₂ sample can be passed through dehumidification tubing352, such as Nafion® polymer tubing, for example. The biofilter 340 andthe optional dehumdification tubing 352 can be used with either theinfrared sensor systems or the Raman sensor systems described above.

Other methods of eliminating moisture problems include employing a heatsink around part or all of the IR optical path, particularly the lenswindow where the IR source passes light. Yet another means includesemploying a water trap or a barrier or filter which is selectivelypermeable to water vapor (moisture) and/or the gases of interest,particularly pCO₂.

It should therefore also be noted that the filter 340 can alsooptionally include a dehumidifying means, e.g., a water vapor filter orremoval medium, either alone or in addition to the biological filter,for allowing any water vapor in the sampling medium or the samplingchamber to disperse in the environment by delivering the mixture thereofpast a water-vapor-permeable wall or medium.

FIG. 15 also schematically illustrates the addition of a gaseoussampling medium pressure sensor and/or regulator 350 (optional) formeasuring the pressure of a gas sampling medium, such as air, forexample, and/or for regulating such pressure to be substantially at somepredetermined pressure level, such as atmospheric pressure, for example,at which the gas analyzer is designed to operate and give accurate,reliable results.

It will be appreciated that the gaseous sampling medium pressure sensorand/or regulator 350 is capable of recording and processing a pressuresignal. Until now there has not been a reliable means for measuringrespiration rate when the patient is breathing on their own. However, inaccordance with the present invention, small pressure changes induced bythe patient's respiration may be derived from the pressure signal toprovide signals indicating respiration rate (RR). For example, if thepressure signal resembles a sine curve, wherein the period of the signalis represented by T, then the respiratory rate=1/T.

It should also be noted that any of the embodiments of the sensorassembly 324 can also include their sensors (other than infrared orRaman) for measuring still other parameters. An example would be aparamagnetic O₂ sensor or Clark-type polarographic O₂ sensor.

It will be appreciated that in a manual system, wherein a syringe isused to draw the gaseous sample into the sensor assembly, it has beenfound to be useful to provide one or more holes 360 in the syringe body362 shown in FIG. 16 in order to allow for pressure regulation andequalization with the atmosphere or some predetermined pressure level.Alternatively, a pressure-difference caused by a pump, with or without apressure regulation or connection device, as needed, can be employed. Inaddition, as is clear from the foregoing discussion, the system can usea single-tube catheter device or a dual-tube version, wherein one tubedelivers the sampling medium to the sampling chamber and the other isused to extract it for measurement.

The gas analyzers described herein, may also be modified in preferredembodiments to make automated regular intermittent or continuousmeasurements of pCO₂ by way of a tonometric catheter. An automatedpumping system may be utilized to withdraw (intermittently orcontinuously) the sample and purge the system. A pressure sensor, suchas that described above, must be available to correct for measuringchamber pressure and to detect balloon inflation and deflation. It willbe appreciated that the gas analyzers will be in communication with acomputer or other peripheral equipment, such as a recorder andinterfaced by standard procedures. The analyzers may be programmed, forexample, through the computer to automatically measure and calculatedesired values. For example, in preferred embodiments, three modes ofoperation are available and may be selected from a menu via the computerkeypad. The following is a description of each mode:

MODE 1: Intramucosal pCO₂ Mode (Default Mode). The instrumentautomatically determines tonometer intramucosal pCO₂ (p₁ CO₂) at pre-setintervals (e.g. every 5 min). A digital display and trend of p₁ CO₂ maybe displayed.

If arterial pCO₂ (p_(a) CO₂) is entered manually via the keypad, apH-gap, defined as pH-gap=(arterial pH-intramucosal pH), will becalculated. The pH-gap will be based on the p₁ CO₂ at the time p_(a) CO₂was measured. A pH-gap trend may be displayed graphically. The p₁ CO₂trend display may also display p_(a) CO₂.

If p_(a) CO₂ and arterial pH (pH_(a)) are both entered, the intramucosalpH (pHi) will be calculated. The pHi will be based on the p₁ CO₂ at thetime the p_(a) CO₂ and pH_(a) were measured. A pHi trend may bedisplayed graphically.

Respiratory rate is calculated from the measured pressure in the balloonwith an in-line pressure sensor described above, and may be displayeddigitally and as a trend.

MODE 2: Dual Operation Mode. In this mode, end-tidal CO₂ (EtCO₂) ismonitored continuously, except when interrupted during each p₁ CO₂ cycle(e.g. approximately 1 min at 5 min intervals). Intramucosal pCO₂ andEtCO₂ may be displayed as two superimposed trend curves.

If arterial pCO₂ (p_(a) CO₂) is entered manually via the keypad, apH-gap, will be calculated. The pH-gap will be based on the p₁ CO₂ atthe time p_(a) CO₂ was measured. A pH-gap trend may be displayedgraphically. The p₁ CO₂ trend display may also display p_(a) CO₂.

If p_(a) CO₂ and arterial pH (pH_(a)) are both entered, the intramucosalpH (pHi) will be calculated. The pHi will be based on the p₁ CO₂ at thetime the p_(a) CO₂ and pH_(a) were measured. The pHi may be displayedgraphically.

MODE 3: End-Tidal CO₂ EtCO₂). The system may also function as a normalEtCO₂ monitor.

It will be appreciated that alarm systems notifying the user of variousabnormal conditions may also be employed in conjunction with the abovesystem. It will further be appreciated that variables such as bodytemperature of the patient, catheter type and elapsed time since bloodgas withdrawal, may also be entered through the keyboard to allow forgreater accuracy in measurements and thus greater accuracy in calculatedvalues and trends. Also, an alternative to manually entering thetemperature, it may optionally be measured by measuring the temperatureof the air sample withdrawn from the tonometric catheter or with athermistor in the balloon, and displayed.

Accordingly, while several preferred embodiments of the invention havebeen disclosed, it will be appreciated that principles of the invention,as set forth in the following claims, are applicable to otherembodiments.

What is claimed is:
 1. A method for determining a parameter which isindicative of the condition of a hollow viscus internal organ in a humanor other mammal, comprising the steps of:(a) placing a catheter having amembrane permeable to carbon dioxide adjacent to the wall of the organ,the condition of which is to be indicated by the determined parameter,so that carbon dioxide associated with the wall of the organ passesacross the permeable membrane; (b) measuring the partial pressure ofcarbon dioxide associated with the wall of the organ; (c) measuring thecarbon dioxide level associated with the blood of said human or othermammal; and (d) determining said parameter by relating saidmeasurements.
 2. A method according to claim 1, wherein the parameter ispCO₂ -gap.
 3. A method according to claim 2, wherein the method furtherincludes the step of generating a visually perceptible representation ofsaid pCO₂ -gap parameter.
 4. A method according to claim 2, includingthe step of recording at least a machine readable representation of saidpCO₂ -gap parameter.
 5. A method according to claim 1, wherein theparameter is pH-gap.
 6. A method according to claim 5, wherein themethod further includes the step of generating a visually perceptiblerepresentation of said pH-gap parameter.
 7. A method according to claim5, including the step of recording at least a machine readablerepresentation of said pH-gap parameter.
 8. A method according to claim5, wherein said pH-gap parameter is integrated over time to assesscumulative effects of tissue damage.
 9. A method according to claim 1,wherein step (a) is further defined as obtaining gas containing carbondioxide from the wall of the organ and wherein step (b) is furtherdefined as subjecting the gas to analysis by infrared detection means.10. A method according to claim 1, wherein step (a) is further definedas obtaining gas containing carbon dioxide from the wall of the organand wherein step (b) is further defined as subjecting the gas toanalysis by Raman spectroscopy means.
 11. A method according to claim 1,further including the step of measuring the pH level associated with theblood of said human or other mammal.
 12. A method according to claim 11,wherein the parameter is pHi, the pH associated with the wall of theorgan, and wherein the determining step relates the measurements ofsteps (b) and (c) and of the pH level associated with the blood todetermine pHi.
 13. A method according to claim 12, wherein the methodfurther includes the step of generating a visually perceptiblerepresentation of pHi.
 14. A method according to claim 12, including thestep of recording at least a machine readable representation of said pHiparameter.
 15. A method according to claim 1, wherein steps (a), (b),and (c) further comprise the steps of placing a catheter having amembrane permeable to oxygen so that oxygen associated with the wall ofthe organ passes across the permeable membrane and of measuring the pO₂associated with the organ wall and with the blood.
 16. A methodaccording to claim 2, wherein steps (a), (b), and (c) further comprisethe steps of placing a catheter having a membrane permeable to oxygen sothat oxygen associated with the wall of the organ passes across thepermeable membrane and of measuring the pO₂ associated with the organwall and with the blood and wherein step (d) is further defined asdetermining a pO₂ -gap parameter by relating the measurements of the pO₂associated with the organ wall and with the blood.
 17. A methodaccording to claim 1, further comprising the step of taking thederivative with respect to time of the measurement of the partialpressure of carbon dioxide associated with the wall of the organ, toassess the rate and direction of change of the measurement.
 18. A methodfor determining a parameter which is indicative of the condition of ahollow viscus internal organ in a human or other mammal in need of suchdetermination comprising the steps of:(a) placing a catheter having amembrane permeable to carbon dioxide adjacent to the wall of the organ,the condition of which is to be indicated by the determined parameter,so that carbon dioxide associated with the wall of the organ passesacross the permeable membrane; (b) measuring the partial pressure ofcarbon dioxide associated with the wall of the organ; (c) estimating thecarbon dioxide level of the arterial blood of said human or other mammalby subjecting said human or other mammal's end-tidal respiration to apCO₂ measurement; and (d) determining said parameter by relating themeasurement of (b) and the estimation of (c).
 19. A method according toclaim 18, wherein the parameter is pCO₂ -gap.
 20. A method according toclaim 19, further including the step of displaying the results of thedetermination of said pCO₂ -gap parameter in a visually perceptibleform.
 21. A method according to claim 19, further including the step ofrecording at least a machine readable representation of said pCO₂ -gap.22. A method according to claim 18, wherein the parameter is pH-gap. 23.A method according to claim 22, further including the step of displayingthe results of the determination of said pH-gap parameter in a visuallyperceptible form.
 24. A method according to claim 22, further includingthe step of recording at least a machine readable representation of saidpH-gap parameter.
 25. A method according to claim 22, wherein saidpH-gap parameter is integrated over time to assess cumulative effects oftissue damage.
 26. A method according to claim 18, wherein step (a) isfurther defined as obtaining gas containing carbon dioxide from the wallof the organ and wherein step (b) is further defined as subjecting thegas to analysis by infrared detection means.
 27. A method according toclaim 18, wherein step (a) is further defined as obtaining gascontaining carbon dioxide from the wall of the organ and wherein step(b) is further defined subjecting the gas to analysis by Ramanspectroscopy means.
 28. A method according to claim 18, wherein step (c)is further defined as subjecting gas comprising the end-tidalrespiration to analysis by an infrared gas analyzer.
 29. A methodaccording to claim 18, wherein step (c) is further defined as subjectinggas comprising the end-tidal respiration to analysis by a Ramanspectrometer.
 30. A method according to claim 18, wherein themeasurement of step (b) and the estimation of step (c) are both carriedout by passing CO₂ -containing gas through an infrared gas analyzer. 31.A method according to claim 18, wherein the measurement of step (b) andthe estimation of step (c) are both carried out by passing CO₂-containing gas through a Raman spectrometer.
 32. A method according toclaim 18, wherein said human or other mammal has been subjected to ananesthetic and wherein the method further includes the step of carryingout an analysis for an anesthetic associated with at least one of thewall of the organ and the end tidal respiration gases.
 33. A methodaccording to claim 18, further including the step of measuring the pHlevel associated with the blood of said human or other mammal.
 34. Amethod according to claim 33, wherein the parameter is pHi, the pHassociated with the wall of the organ, and wherein the determining steprelates the measurement of step (b) and the estimation of step (c) andthe pH level associated with the blood to determine pHi.
 35. The methodaccording to claim 34, further including the step of generating avisually perceptible representation of said pHi parameter.
 36. A methodaccording to claim 34, further including the step of recording at leasta machine readable representation of said pHi parameter.
 37. (amended) Amethod according to claim 18, wherein steps (a), (b), and (c) furthercomprise the steps of placing a catheter having a membrane permeable tooxygen so that oxygen associated with the wall of the organ passesacross the permeable membrane, of measuring the pO₂ associated with theorgan wall and estimating the pO₂ of the arterial blood by subjectingsaid human or other mammal's end-tidal respiration to a pO₂ measurement.38. A method according to claim 37 wherein step (d) is further definedas determining a pO₂ -gap parameter by relating the measurement of thepO₂ associated with the organ wall and the estimation of the arterialblood pO₂.
 39. A method according to claim 18, further comprising thestep of taking the derivative with respect to time of the measurement ofthe partial pressure of carbon dioxide associated with the wall of theorgan, to assess the rate and direction of change of the measurement.40. A method according to claim 32 wherein the step of carrying out ananalysis is further defined as analyzing for N₂ O.
 41. A methodaccording to claim 1 wherein said human or other mammal has beensubjected to an anaesthetic and wherein the method also includes thestep of carrying out an analysis for an anaesthetic.
 42. A methodaccording to claim 41 wherein the step of carrying out an analysis isfurther defined as analyzing for N₂ O.
 43. A method for determining apO₂ -gap parameter which is indicative of the condition of a hollowviscus internal organ in a human or other mammal, comprising the stepsof:(a) placing a catheter having a membrane permeable to oxygen adjacentto the wall of the organ so that oxygen associated with the wall of theorgan passes across the permeable membrane; (b) measuring the pO₂associated with the wall of the organ; (c) measuring the pO₂ levelassociated with the blood of said human or other mammal; and (d)determining said pO₂ -gap parameter by relating said measurements.
 44. Amethod according to claim 43, wherein the method further includes thestep of generating a visually perceptible representation of pO₂ -gap.45. A method according to claim 44, including the step of recording atleast a machine readable representation of said pO₂ -gap.
 46. A methodaccording to claim 43 wherein the step of measuring the pO₂ levelassociated with the blood of said human or other mammal is furtherdefined as obtaining the measurement from an estimation of the oxygenlevel of the arterial blood of said human or other mammal obtained fromsubjecting said human or other mammal's end-tidal respiration to a pO2measurement.
 47. A method for determining at least one parameter whichis indicative of the condition of a hollow viscus internal organ in ahuman or other mammal, comprising the steps of:(a) placing a catheterhaving a membrane permeable to carbon dioxide and oxygen adjacent to thewall of the organ so that carbon dioxide and oxygen pass across thepermeable membrane; (b) measuring the partial pressure of carbon dioxideand the partial pressure of oxygen associated with the wall of theorgan; (c) measuring the carbon dioxide level, the oxygen level, and thepH associated with the blood of said human or other mammal; and (d)determining said parameter by relating said measurements, said parametercomprising at least one of pCO₂ -gap, pO₂ -gap, pH-gap, and pHi, the pHassociated with the wall of the organ.